Fenton, TR;
Nathanson, D;
Ponte de Albuquerque, C;
Kuga, D;
Iwanami, A;
Dang, J;
Yang, H;
... Furnari, FB; + view all
(2012)
Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240.
PNAS USA
, 109
(35)
14164 - 14169.
10.1073/pnas.1211962109.
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Abstract
Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.
| Type: | Article |
|---|---|
| Title: | Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240 |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.1211962109 |
| Publisher version: | http://dx.doi.org/10.1073/pnas.1211962109 |
| Language: | English |
| Additional information: | PMCID: PMC3435194 |
| Keywords: | Animals, Astrocytes, Brain Neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Disease Models, Animal, Drug Resistance, Neoplasm, Glioblastoma, Humans, Mice, Mice, Mutant Strains, Mice, Nude, PTEN Phosphohydrolase, Phosphorylation, Protein Kinase Inhibitors, Quinazolines, Receptor, Epidermal Growth Factor, Signal Transduction, Transplantation, Heterologous, Tumor Cells, Cultured, Tyrosine |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1378741 |
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